Most of the traditional drugs used for treating cancers, e.g., taxanes such as paclitaxel and doxetaxel; vinca alkaloid such as vincristine, vinblastine and vinorelbin; anthracyclines such as daunomycin and doxorubicin; camptothecins such as topotecan, irinotecan; actinomycin; and etopocid are based on selective cytotoxicity, but such selectivity against cancer cells has been unsatisfactory to cause many side effects.
To overcome such a problem, recent studies have focused on specific molecular level targets in the cell to maximize the therapeutic effect of an anticancer agent without causing adverse side effects.
In cells, there are many signal transduction systems, which are functionally linked to each other to control the proliferation, growth, metastasis and apoptosis of cells. A breakdown of the intracellular controlling system by genetic and environmental influences may cause abnormal amplification or destruction of the signal transduction system so that the possibility for tumor cell generation occurs.
Protein tyrosine kinases play important roles in such cellular regulation, and their abnormal expression or mutation has been observed in cancer cells. Protein tyrosine kinase is an enzyme which catalyzes the transportation of phosphate groups from ATP to tyrosines located on the protein substrate. Many growth factor receptor proteins function as tyrosine kinases to transport cellular signals. The interaction between growth factors and their receptors normally controls the cellular growth, but abnormal signal transduction caused by the mutation or overexpression of any of the receptors may induce tumor cells or cancers.
Protein tyrosine kinases have been classified into many families in terms of growth factors, and epithelial cell growth factors (EGFs)-related EGF receptor (EGFR) tyrosine kinase have been intensely studied. An EGFR tyrosine kinase is composed of a receptor and tyrosine kinase, and delivers extracellular signals to the cell nuclear through the cellular membrane. The EGFR tyrosine kinases are classified by their structural differences into EGFR (Erb-B1), Erb-B2, Erb-B3, Erb-B4, and all of the above members can form a homodimer- or heterodimer-signal delivery complex. Also, overexpression of more than one member of the above mentioned homodimers is often observed in malignant cells.
Therefore, the inhibition of mutated or overexpressed EGFR tyrosine kinases has been considered to be useful for treating tumors, and many drugs have been developed therefor, e.g., Gefitinib, Erlotinib, Camertinib, Lapatinib.
International Patent Publications WO 96/033981, WO 96/033979, WO 97/038994 and WO 96/033980 each discloses a quinazoline derivative substituted with an alkoxyalkylamino or alkylaminoalkoxy group, International Patent Publications WO 97/030034 and WO 96/016960 each discloses quinazoline substituted with aryl or heteroaryl, and International Patent Publications WO 2003/040109 and WO 2003/040108 disclose compounds having aminoalkoxy substituents at position 5 of quinazoline (Nomenclature of quinazoline is according to a reference [J. A. Joule, Chapman & Hall, Heterocyclic chemistry, 3rd Ed., 189]).
International Patent Publication WO 95/019970 and U.S. Pat. Nos. 5,654,307 and 5,679,683 each discloses various tricyclic heteroaryl compounds, International Patent Publications WO 99/006396, WO 99/006378, WO 97/038983, WO 2000/031048, WO 98/050038, WO 99/024037 and WO 2000/006555, and European Patent 787722 each discloses quinazoline compounds that inhibit the tyrosine kinase irreversably, U.S. Pat. No. 6,225,318, European Patents 0387063 and 01292591, and International Patent Publications WO 2001/098277, WO 2003/045939 and WO 2003/049740 each discloses compounds having various alkenyl or alkynyl substituents at position 6 of quinazoline.
Also, International Patent Publications WO 98/043960, WO 2000/018761, WO 2001/047892, WO 2001/072711, WO 2003/050090, WO 99/09016, WO 2000/018740 and WO 2000/66583 disclose 3-cyanoquinoline compounds, International Patent Publications WO 98/002434, WO 98/002437, WO 99/035132, WO 99/035146, WO 2001/004111 and WO 2002/002552 each discloses various quinazoline compounds substituted with furan having various sulfonealkylamino substituents, and International Patent Publications WO 2003/053466 and WO 2001/094353 disclose specific thienopyrimidine compounds.
Further, International Patent Publications WO 2001/012227, WO 2004/014386, WO 2004/035057 and WO 2001/076586 disclose various methods for treating tumors that employ specific drugs that interact with EGFR tyrosine kinase in combination with radiation therapy.
However, the above mentioned conventional quinazoline derivatives have to be taken in large dose for intended treatments, which causes such side effects such as diarrhea and skin eruption. Accordingly, there has continued to exist a need to develop an effective drug that gives no adverse side effect.